Splicing dysregulation in glioblastoma alters the function of cell migration-related genes.

IF 5.4 2区医学 Q1 NEUROSCIENCES

Glia Pub Date : 2024-10-24 DOI:10.1002/glia.24630

Minu Seong, Pedro Bak-Gordon, Zhaoqi Liu, Peter D Canoll, James L Manley

{"title":"Splicing dysregulation in glioblastoma alters the function of cell migration-related genes.","authors":"Minu Seong, Pedro Bak-Gordon, Zhaoqi Liu, Peter D Canoll, James L Manley","doi":"10.1002/glia.24630","DOIUrl":null,"url":null,"abstract":"<p><p>Glioblastoma (GBM) has a poor prognosis with a high recurrence and low survival rate. Previous RNA-seq analyses have revealed that alternative splicing (AS) plays a role in GBM progression. Here, we present a novel AS analysis method (Semi-Q) and describe its use to identify GBM-specific AS events. We analyzed RNA-seq data from normal brain (NB), normal human astrocytes (NHAs) and GBM samples, and found that comparison between NHA and GBM was especially informative. Importantly, this analysis revealed that genes encoding cell migration-related proteins, including filamins (FLNs) and actinins (ACTNs), were among those most affected by differential AS. Functional assays revealed that dysregulated AS of FLNA, B and C transcripts produced protein isoforms that not only altered transcription of cell proliferation-related genes but also led to enhanced cell migration, resistance to cell death and/or mitochondrial respiratory function, while a dysregulated AS isoform of ACTN4 enhanced cell migration. Together, our results indicate that cell migration and actin cytoskeleton-related genes are differentially regulated by AS in GBM, supporting a role for AS in facilitating tumor growth and invasiveness.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":""},"PeriodicalIF":5.4000,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Glia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/glia.24630","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

Glioblastoma (GBM) has a poor prognosis with a high recurrence and low survival rate. Previous RNA-seq analyses have revealed that alternative splicing (AS) plays a role in GBM progression. Here, we present a novel AS analysis method (Semi-Q) and describe its use to identify GBM-specific AS events. We analyzed RNA-seq data from normal brain (NB), normal human astrocytes (NHAs) and GBM samples, and found that comparison between NHA and GBM was especially informative. Importantly, this analysis revealed that genes encoding cell migration-related proteins, including filamins (FLNs) and actinins (ACTNs), were among those most affected by differential AS. Functional assays revealed that dysregulated AS of FLNA, B and C transcripts produced protein isoforms that not only altered transcription of cell proliferation-related genes but also led to enhanced cell migration, resistance to cell death and/or mitochondrial respiratory function, while a dysregulated AS isoform of ACTN4 enhanced cell migration. Together, our results indicate that cell migration and actin cytoskeleton-related genes are differentially regulated by AS in GBM, supporting a role for AS in facilitating tumor growth and invasiveness.

查看原文本刊更多论文

胶质母细胞瘤中的剪接失调会改变细胞迁移相关基因的功能。

胶质母细胞瘤（GBM）预后不良，复发率高，存活率低。以前的 RNA-seq 分析显示，替代剪接（AS）在 GBM 的进展中起着一定的作用。在这里，我们介绍了一种新的 AS 分析方法（Semi-Q），并描述了该方法在识别 GBM 特异性 AS 事件中的应用。我们分析了来自正常大脑（NB）、正常人类星形胶质细胞（NHA）和 GBM 样本的 RNA-seq 数据，发现 NHA 和 GBM 之间的比较尤其具有参考价值。重要的是，这项分析发现，编码细胞迁移相关蛋白（包括丝蛋白（FLNs）和肌动蛋白（ACTNs））的基因是受差异AS影响最大的基因之一。功能测试显示，FLNA、B 和 C 转录本的 AS 失调产生的蛋白质同工型不仅改变了细胞增殖相关基因的转录，还导致细胞迁移、抗细胞死亡和/或线粒体呼吸功能增强，而 ACTN4 的 AS 失调同工型增强了细胞迁移。总之，我们的研究结果表明，GBM 中的细胞迁移和肌动蛋白细胞骨架相关基因受 AS 的不同调控，支持 AS 在促进肿瘤生长和侵袭性方面的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Glia 医学-神经科学

CiteScore

13.10

自引率

4.80%

发文量

162

审稿时长

3-8 weeks

期刊介绍： GLIA is a peer-reviewed journal, which publishes articles dealing with all aspects of glial structure and function. This includes all aspects of glial cell biology in health and disease.